Cardiac arrhythmias continue to be a leading cause of death and disability. Despite this alarming fact, a noninvasive imaging modality (analogous to CT or MRI) for cardiac electrophysiology and arrhythmia has not been available for clinical diagnosis and guidance of therapy. Importantly, such imaging modality is also greatly needed for the study of arrhythmia mechanisms in humans, where the arrhythmic substrate and disease processes differ considerably from those in experimental animal models. During the current grant period, we have made the transition from the development, implementation and validation of a novel noninvasive imaging modality (Electrocardiographic Imaging, ECGI) to its first successful applications in the study of human cardiac electrophysiology and arrhythmia. In the next period of support, we will apply ECGI to study arrhythmic substrates, mechanisms and outcomes of therapy in selected disorders of clinical importance and scientific interest. Goals for the next period are: (1) to study the mechanisms of persistent atrial fibrillation and to follow pot-ablation changes over time in the atrial electrophysiologic substrate and activation patterns, including recurrences of atrial arrhythmias. (2) To investigate the mechanisms of cardiac repolarization abnormalities associated with arrhythmias and sudden death. Two arrhythmogenic syndromes will be investigated: Long QT and Early Repolarization. (3) To investigate the coupling between electrical excitation and mechanical contraction in the normal human heart, its alteration in heart failure and modification by cardiac resynchronization therapy (CRT) in the failing heart. PUBLIC HEALTH RELEVANCE: An estimated 400,000 Americans die each year from erratic heart rhythms, and many more are disabled (estimated annual fatalities worldwide is seven million). The proposed research is aimed at studying arrhythmia properties and mechanisms in humans, using a novel noninvasive imaging modality for cardiac arrhythmias (Electrocardiographic Imaging, ECGI) developed in our laboratory.